Medical advances over the last century have enabled people to live longer and remain healthy for a significantly greater amount of time. It is critical that clinicians understand the changes that occur in various organ systems with aging if we are to achieve improvements in the care of the elderly patient. Significant alterations occur in the gastrointestinal (Gl) tract with aging, which can manifest as impairments in physiologic functions, such as alterations in growth, secretion, motility, and response to trophic factors. These changes have direct ramifications to diseases that are more common in the elderly, such as the development of Gl malignancies. Relatively few studies have rigorously examined the changes that occur in the Gl tract with aging. In the past, our laboratory has made great strides in the better understanding of the physiologic changes that occur in the Gl tract with aging. We have identified important functional alterations that occur with age, such as dysregulation of gut mucosal function and growth in response to trophic factors. Recently, we have shown that the basal proliferative rate of colonic mucosa is increased in aged mice. We have utilized gene array analysis and protein expression studies to demonstrate changes in the expression of components of the phosphatidylinositol-3 kinase (PI3K) pathway and insulin-like growth factor (IGF) proteins in the intestine with aging. In addition, we have identified an important role for the PI3K/Akt pathway in normal intestinal function and proliferation. Based on our findings, the central hypothesis of this proposal is that aging results in the increased activation of the PI3K/Akt pathway in the colon and this increased activity results in increased basal proliferation. We postulate that local changes in downstream protein expression and altered proliferative activity may predispose these colonic crypts to malignant transformation. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) To define the age-associated alteration of colonic growth and PI3K/Akt pathway activation; 2) To determine alterations in proliferation and expression patterns of isolated colonic crypts and stem cells with aging; and 3) To elucidate the role of IGF-I and its receptor on altered PI3K/Akt expression and proliferation. Our studies, utilizing novel in vitro models and molecular techniques, will continue to challenge previous concepts and viewpoints regarding the aging process and address clinically relevant questions of Gl health and disease with aging, which will translate to a better understanding of the effects of aging on the Gl tract and possibly lead to novel therapies.